CANCER TRIALS: the breakthrough treatments giving families hope
Nobody would consider the parents of children with cancer lucky, but for two families who were included in a ground-breaking program to fight childhood cancers, lucky is exactly how they feel. Genevieve Gannon meets those families.
Luck has moved through the lives of Mina and Rob Caterjian in a most capricious way. They struggled to conceive and suffered several miscarriages over eight years until they welcomed a brown-eyed daughter with a loving and curious personality. For 11 months, their lives felt full of happiness and good fortune, until fate turned again and they received the grave news their little girl, Ellie, had a rare and aggressive cancer. The doctors were despairing that there was nothing they could do when their luck changed again: Ellie was accepted into a new research program using DNA sequencing to develop treatment targeted to her cancer’s speci c genetic mutation. It was still a long shot at a cure, but for Rob and Mina it was hope. The Zero Childhood Cancer Program had just opened and Ellie was among the rst acutely sick Australian children to be included.
“Had Ellie been born a year prior, this wouldn’t have been available,” says Mina. “As she was leaving the ICU the doctor said, this is a miracle.”
Ellie was chosen for the Zero pilot program of just 12 children – later expanded to 58 – to have her cancer analysed by a team of experts using the very latest technology. Sitting in a café, Mina recounts how giving birth had felt like the end of their struggles, not realising what lay ahead.
“We thought, we can do anything because we nally have our child,” Mina says. “Then we noticed she wasn’t meeting her milestones. She was losing weight. I kept going back to the GP. We were told things like, ‘You’ve changed formula; she’s not used to it. She’s got re ux’.”
But Mina knew it was more than that. In six weeks, Ellie had 11 medical appointments before one doctor recognised the warning signs. “He took off her clothes, had one look at her and said, ‘We need to do an X-ray. I’m going to call your husband.” Immediately Mina realised something was seriously wrong. “I raced her downstairs,” she said.
Soon Mina and Rob were standing in front of the X-ray images. “I saw Rob’s jaw drop. I said, ‘What is it?’ The doctor said, ‘See that? That’s not supposed to be there’.”
A nefarious white mass was blotting out Ellie’s lung. Growing inside her tiny chest was a tumour the size of a football.
“The doctor said, ‘You need to race her straight to Sydney Children’s Hospital. Just go.’ We were in tears,” Mina says. “We were in the Emergency Department for hours because they didn’t know what to do. They didn’t know what type of tumour it was.”
At 11 months, Ellie had springy curls and an inquiring mind. While her parents had grave discussions with oncologists and specialists, she’d squirm out of her mother or father’s arms and investigate the doctor’s of ce. During one appointment a security guard rushed into the room because she’d crawled under a desk and pressed the duress alarm. Mina smiles recounting the story. She and Rob couldn’t believe their spirited little one had cancer. But there was worse to come.
“In that rst week, we had a surgeon come in. He said, ‘We can look at de-bulking it but the only problem will be I don’t know what position she’ll be left in when I cut it out. I just don’t want to take the risk.’” He suggested a course of chemotherapy to try to shrink the tumour, but scarily, the chemo did nothing. In fact, the deadly mass grew larger. The doctors still didn’t know exactly what they were dealing with. Meanwhile, Ellie was becoming weaker.
“Her breathing had been compromised. The tumour actually shifted her heart and trachea to the other side,” Mina says. “I was so distressed. I said, ‘Please, she’s my only child. Please make sure she comes out of this.’”
A biopsy showed Ellie’s cancer to be even rarer than rst thought. Her type of tumour normally grows on limbs and protrudes from the body. Ellie’s was on the connective tissue inside her rib cage, which is what allowed it to lurk undetected for so long.
“Her oncologist said he’d only seen one in 30 years,” Mina explains. “So it was a big shock. I was confused. Can it be treated with chemo? Can’t you just cut it out? When the surgeon said it was too large, we thought, this isn’t how things are supposed to work. We were told to take one day at a time and to me that’s always ominous because that doesn’t sound good at all.”
There was one hope. If the Zero Childhood Cancer Program could identify exactly what was causing the cancer, they might be able to match it with a drug. “They said, if it’s what we think it is, there’s a trial drug we can use to treat it,” Mina remembers. But there was still a long road ahead.
Ellie’s story
Every year, thousands children or young people around the world are diagnosed with cancer, plunging their families into the same fear and uncertainty Mina and Rob felt after Ellie’s diagnosis. For some, they face the grim prospect of limited or no treatment options. Until now.
Zero Childhood Cancer was set up to develop a precision treatment regime which aims to understand each child’s cancer at a genomic level in order to find the medication to target the unique mutation.
“Precision medicine is about trying to take the trial and error out of treating patients,” says program leader Vanessa Tyrrell.
Historically, she explains, treating cancer was about trying to match one type of cancer to the best type of treatment from what was on offer.
“For example, you have 10 children with sarcoma. Two of them have this kind of sarcoma; we know how to treat that. Eight of them have sarcomas that are all a bit different.”
What Zero does is look at the genomics (genetic make-up) of those eight sarcomas that are “a bit different”.
“We look and we say, ‘Those three all have very similar genomics. They’ve got the same target. They might respond to the same drug.’ But then there’s another four we actually don’t know and it turns out all four of them have different genomic signatures. So, everybody’s signature is different, each of their tumours, their signature is different. They have different targets and therefore might respond differently to different drugs.”
When Ellie’s sample arrived at Zero’s state-of-the-art lab in Sydney, it went through the process the team had built from scratch after they were granted funding in 2015.
“Once we receive a child’s tumour and their blood, we isolate or extract the DNA and RNA,” Vanessa says. That is then used to replicate the child’s tumour. One of the ways they do this is by giving a mouse the exact same cancer as the child. “We want to see if the tumour will respond to certain drugs and whether it is likely to be a potential option for the children. This can take many, many months.”
While this is happening, the data from the genomic testing is returned for analysis. To the untrained eye, the data looks like a circular colour chart you’d see in a school art class. It provides a visual representation of possible mutations that could be causing cancer.
The team looking at Ellie’s colour chart were able to see a mutation at the NTRK3 gene. This was another stroke of luck for Ellie, Mina and Rob.
“They said yes, she can use this style of drug,” says Mina. “Thank God! Then the clinicians went to work trying to get that drug into the country.”
“They said yes, she can use this drug. Thank God!”
A key part of what Zero does is collaborate with other labs around the world to find and improve access to new and emerging treatments.
“If the drug’s not available, if there’s not a clinical trial open, if there’s not a paediatric dose, then in a sense you’re not affecting that change because you can’t access the drug,” tells Vanessa.
Fortunately, Ellie was able to access larotrectinib, a sweet syrup administered orally. It had the added appeal of being less toxic than other cancer treatments. “Your hair still grows, you don’t have any stomach issues and you don’t get ulcers in your mouth,” Mina explains.
Ellie started on the drug the day before she turned one. The next day, Mina asked the ICU nurse if they could wake her up from the sedation to celebrate her first birthday. “We had the Starlight [Children’s Foundation] crew come down from upstairs. They had drawn these massive pictures of elephants and giraffes, and they were singing. They were crying, I was crying, the family was crying. They had cakes for her as well. I thought, ‘Please let this trial drug work. Please let it work!’”
Within weeks, Ellie’s tumour had started to shrink. Ellie was able to go home, where her parents continued to give her larotrectinib, then brought her back for scans and X-rays every six weeks to monitor her tumour.
Vanessa says Ellie has been a wonderful story, but she cautions that, at the moment, the chances of being able to cure a child with a very aggressive cancer are still low, and she doesn’t want to give false hope.
“But certainly, yes, being able to be enrolled in this program
– for a child with a very high-risk cancer with very limited treatment options – it does provide an element of hope and has extended the lives of some of these children.”
Where there’s life ...
By the middle of September 2017, Ellie’s tumour had shrunk to half its original size. Her surgeon told Mina and Rob he’d never seen anything like it. Ellie had gone from listless and weak to sitting up and wanting food. Once she was home, her parents patiently administered the drug and watched the tumour shrink further. “By the time she was three, she wanted to administer it herself,” Mina laughs.
When the tumour was no bigger than a marble, the surgeon said it was time to remove it. In December last year, when Mina took Ellie for a follow-up consultation, the oncologist had good news: genetic testing had shown Ellie’s cancer was not prone to mutation.
“I said, ‘What does that mean?’” Mina recalls. “He said, ‘Well, she’s cancer free!’”
Little Ellie did what all cancer patients dream of: she rang the bell that signi ed her treatment was done. Although, Mina jokes, she didn’t quite understand what was happening. “She looked like, ‘What is happening? Why am I ringing this bell?’” she laughs.
As Ellie’s personalised treatment was shrinking her tumour, back home, Thomas and his family endured a tense wait. “I remember the day we went in and they said they’d come up with potential solutions. It was exactly what we needed to hear,” Abigail says.
An oncologist showed them Thomas’ DNA sequence and how they had mapped it to a particular trial medication they thought would work.
“You could see the excitement and passion in her explaining it and that lled our hearts with con dence,” tells John.
At rst, Thomas didn’t take that well to the medication and they had to take a break, but it wasn’t long before he started showing signs of improvement. When John was shown Thomas’ pre-trial scan and his new scan side-by-side, he could see the tumour mass had shrunk signi cantly.
“I just sat there crying, looking at the screen,” he says. Then he called Abigail and she cried too.
“It had only been two months on the treatment and unexpectedly an amazing result,” says Abigail. “We had been told, at best, he won’t get any worse. To see so much progress in such a short period, it was life-saving. Tears, tears.”
Thomas’ scans are still stable and Abigail says the family just enjoyed the best summer in years.
“He was active, vibrant and energetic. He’s slumped a little with the return of school, but he’s not on pain medication all the time. He’s able to enjoy things he hadn’t previously.”
A clinical trial of Ellie’s drug is now open to all Australian children whose cancer is identi ed by Zero as having the same genetic marker. By 2023, Zero wants every single Australian child diagnosed with cancer to have their disease sequenced and analysed.
Vanessa emphasises it’s still early days, but the small amount of data from the rst 250 children has been promising. “Again, tempering my message, that was a very small number of children with limited clinical response data, but we’re hoping we’ll see a trend over time,” she says.
For the families, however, the precious time the trial has brought them is nothing short of a miracle. Mina says she feels her family has been blessed, as Ellie, now a lively four-year-old, plays happily nearby.
“It is an amazing program,” she says.
John agrees. “I often say it’s extremely unlucky to be in the situation we are. But I consider us even luckier to be where we are now.”